Pseudopeptides

The dimethoxybenzyl group was used for backbone protection of the pseudopeptides of the form Xaai/r(CH2N)Gly (Xaa = amino acid). It is introduced by reductive alkylation with the aldehyde and NaCNBH3. Acidolysis with TFMSA in TFA/thioanisole is used to remove it from the amine, but the efficiency is dependent upon the peptide sequence. ... 

Application of the bromine substitution reaction allows the synthesis of aminoamides, alkoxyamides of simple alcohols and sugars, depsipeptides and (NH) pseudopeptides, C2 symmetric compounds. 

Nielsen P.E., Haaima G. Peptide nucleic acid (PNA). A DNA mimic with a pseudopeptide backbone. Chem. Soc. Rev. 

In peptide chemistry, the term "pseudopeptide" is commonly used to denote a peptide in which some or all of the amino acids are linked together by bonds other than the conventional peptide Linkage (13). Such pseudopeptides have found applications as specific structural... 

Caliendo G et al. (1999) Synthesis and biological activity of pseudopeptide inhibitors of Ras farnesyl transferase containing unconventional amino acids. Farmaco 54(11-12) 785-790... 

Pseudopeptidic Hydroxamic Acids and N-formyl-N-hydroxylamines Non-peptidic Templates... 

Schiller PW, Weltrowska G, Nguyen TM-D, Wilkes BC, Chung NN, Lemieux C. TIPPpP] a highly potent and stable pseudopeptide opioid receptor antagonist with extraordinary selectivity. J Med Chem 1993 36 3182-3187. 

Oxadiazole amine 174 serves as an excellent template for the introduction of a wide variety of 5-amido side chains onto the 1,2,4-oxadiazole nucleus (Equation 26), and several such products 175 are potent inhibitors of the tyrosine kinase ZAP-70 <1999BML3009>. Amide or pseudopeptide side chains can also be introduced by the... 

The present chapter focuses on specific aspects of these challenges, namely peptide bond hydrolysis (chemical and enzymatic) and intramolecular reactions of cyclization-elimination (Fig. 6.4). This will be achieved by considering, in turn a) the enzymatic hydrolysis of prodrugs containing a peptide pro-moiety (Sect. 6.2), b) the chemical hydrolysis of peptides (Sect. 6.3), c) the enzymatic hydrolysis of peptides containing only common amino acids (Sect. 6.4), d) the hydrolysis of peptides containing nonproteinogenic amino acids (Sect. 6.5), and, finally, e) the hydrolysis of peptoids, pseudopeptides and peptidomimetics (Sect. 6.6). 

Pseudopeptides are not always clearly defined in the literature. Here, we use the term to mean compounds with a modified peptide backbone, namely with some or all peptide bonds replaced by bioisosteric surrogates. 

Much has been published on the design, synthesis, and activities of pep-toids, pseudopeptides, and peptidomimetics. In contrast, published reports on their biological stability, metabolism, and pharmacokinetics are scarce, making it currently impossible to draw robust conclusions or even to delineate sound trends. This is an unfortunate situation given the vast amount of data that remains buried in industrial archives. 

As stated above, we define pseudopeptides as compounds having a modified peptide backbone, namely with at least one peptide bond replaced by a bioisosteric surrogate (summarized in Table 6.7) [139][181][234], Such surrogate groups are nonhydrolyzable by nature, or hydrolyzable only under severe conditions in the case of the S02-NH bond. In the vast majority of published pseudopeptides, only one or a very few peptide bonds had been replaced and most monomeric units are amino acids, meaning that such pseudopeptides do qualify as peptides. 

Table 6.7. Examples of R-CONH-R Peptide-Bond Surrogates Used in Pseudopeptides... 

An example of a pseudopeptide containing the CH2-NH group is afforded by N/t9,CH2-NH brady kinin. This analogue was stabilized not only against carboxypeptidase, which cleaves bradykinin at the 8,9-position, but also against ACE, which cleaves it at the 7,8-position (see Table 6.6). 

Fig. 6.41) in rats [238], This pseudopeptide, which contains a CHOHCH2 surrogate replacing the 3,4-peptide bridge, was developed as an... 

Fig. 6.41. Metabolic fate of the pseudopeptide SK F 107461 (Cbz-Ala-AH-Phei/ CHOHCHJ-Gly-Val-Val-OMe, 6.114) in rats [238], The six residues are numbered as shown above the structure. The arrows marked 1 and 2 indicate the primary and subsequent sites of hydrolysis, respectively. Compound 6.115 was the smallest and most polar metabolite detected.

It is interesting to note that the tetrahydroisoquinolinyl motif (see Fig. 6.42,c) has already been encountered in Hoe 140 (6.94) during discussion of artificial residues (Sect. 6.5.2). Similarly, the cyclopropane-derived pepti-domimetic motif shown in Fig. 6.42,c [241] could also be classified as a pseudopeptide fragment. These examples show that some overlap in the definitions used here is unavoidable. 

J. L. Fauchere, C. Thurieau, Evaluation of the Stability of Peptides and Pseudopeptides as a Tool in Peptide Drug Design , in Advances in Drug Research , Vol. 23, Ed. B. Testa, Academic Press, London, 1992, p. 127- 159. 

G. J. Anderson, Incorporation of Stable Pseudopeptide Bonds , in Methods in Molecular Biology, Neuropeptide Protocols , Eds. G. B. Irvine, C. H. Williams, Humana Press, Totowa NJ, 1997, p. 49-60. 

Y. Crozet, J. J. Wen, R. O. Loo, P. C. Andrews, A. F. Spatola, Synthesis and Characterization of Cyclic Pseudopeptide Libraries Containing Thiomethylene and Thiomethy-lene-sulfoxide Amide Bond Surrogates , Mol. Discov. 1998, 3, 261-276. 

D. E. Benovitz, A. F. Spatola, Enkephalin Pseudopeptides Resistance to in vitro Proteolytic Degradation Afforded by Amide Bond Replacements Extends to Remote Sites , Peptides 1985, 6, 257 - 261. 

J. P. Meyer, T. J. Gillespie, S. Horn, V. J. Hruby, T. P. Davis, In vitro Stability of Some Reduced Peptide Bond Pseudopeptide Analogues of Dynorphin A , Peptides 1995, 16, 1215-1219. 

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